An Update on Regulatory and Clinical Efforts en route to Commercialization of Cyclotron-Produced Tc-99m KR Buckley1, M Cross2, T Besanger2, S Foster1,2, F Gleeson1,2, J Schlosser1,2, J Hanlon1,2, A Celler1, M Dodd1, V Hanemaayer1, B Hook1, X Hou1, J Kumlin1, S McDiarmid1, FS Prato1, L Stothers1, J Tanguay1, JF Valliant1, M Vuckovic1, S Zeisler1, F Bénard1, M Kovacs1, T Ruth1, P Schaffer1,2 1) The ITAP Consortium 2) ARTMS Products, Inc. Sept. 13th, 2016

Current Supply Model

Reactor Mo-99 Processer Generator Manufacturer Radiopharmacy Clinic 2

Our Philosophy

Cyclotron + ARTMS Technology Clinic Radiopharmacy 3

Cyclotrons by the Numbers

P Schaffer, F. Benard, A. Berstein et al. Phys Proc. 2015, 66, 383. 4

Cyclotron Ground transport Air transport

• Decentralized Production – 99mTc locally produced, locally used, competitively priced – Redundant supply to avoid widespread shortages – Fits with existing radiopharmacy distribution model – Complementary to:

• other medical isotopes produced by cyclotrons (18F) • other sources of 99mTc

Canadian Perspective

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2009 to Present: NRCan Mandate

100Mo Target

Goals: • Demonstrate routine, reliable, commercial-scale production of 99mTc via

100Mo(p,2n) at multiple sites, multiple brands; • Obtain regulatory approval for clinical use in humans; • Establish a business plan; • Disseminate, commercialize the technology

Hypothesis: Future production will be from variety of sources (neutron, proton,

electron) and market driven

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

100Mo Recovery

6 J. Beaver, H. Hupf, J Nucl Med 1971;12:739-741

Different Machines, Different Capabilities

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100Mo Target Manufacturing

100Mo Target

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

Schaffer et al. Phys. Proc. 2015,66,383. Zeisler et al. WTTC 2014

Bénard et al., J. Nucl. Med. 2014, 55, 1017.

Press-Sinter-Braze Electrophoretic deposition

• Maximize 99mTc production, minimize impurities: 100Mo purity, target thickness, irradiation energy/time

• Reduce density, balance thermal conductivity

100Mo Recovery

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Cyclotron Retrofit

100Mo Target

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

100Mo Recovery

PETtrace

300 µA, 18 MeV, 5.4 kW

TR30 TR19

450 µA, 24 MeV, 10.8kW

130 µA, 16.5 MeV, 2.1 kW

Real and Projected Yields of 99mTc 100Mo Target

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

100Mo Recovery

TR19 18 MeV, 300 μA

Theoretical 15.4 Ci (6h) Achieved 15.0 Ci (@ 300 µA) Expected Satn: 103 mCi/µA

GE PETtrace 16.5 MeV, 130 μA

Theoretical 4.9 Ci (6h) Achieved 4.7 Ci

Expected Satn: 75.6 mCi/µA

TR30 (@24 MeV) 24 MeV, 500 μA

Theoretical 39 Ci (6h) Achieved ~32 Ci (@ 450 µA) Expected Satn: 156.8 mCi/µA

Purification of 99mTc 100Mo Target

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

100Mo Recovery

Morley et al. Nuc. Med. Biol. 2012, 551-559 Bénard et al., J. Nucl. Med. 2014, 55, 1017-1022

• Target Dissolution • Target transfers pneumatically

for dissolution • 30% H2O2 circulated with

peristaltic pump • 5M NaOH added and circulated • 45 minutes • Transferred to processing

module for MoO42- / TcO4

- separation

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Purification of 99mTc 100Mo Target

Cyclotron Modification

Optimize Irradiation

Purify 99mTcO4

Regulatory QA/QC

100Mo Recovery

Morley et al. Nuc. Med. Biol. 2012, 551-559 Bénard et al., J. Nucl. Med. 2014, 55, 1017-1022

Purification: • Solid-phase extraction • Process Time: ~45 min. • Efficiency: 92.7 ± 1.1% • Final Product: Na[99mTcO4] • GMP compliant

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Tc impurities

Mo impurities

Other reactions

Target backing J. Tanguay et al, Phys Med Biol. 2015 Nov 7 ; 60(21) pp 8229-47

Nuclear Impurities

Element Content (ppm)

Mn 0.1 Cr 1.16 Cu 5 Fe 16 Sn 1.8 Ni 0.5 Si 15 Na 6 Mg 1 Ti 0.26 Al 2.16 Co 0.1 Zn 1 W 14

Chemical Impurities

Isotope Content (%)

100Mo 99.815

98Mo 0.17

97Mo 0.003

96Mo 0.003

95Mo 0.003

94Mo 0.003

92Mo 0.003

Isotopic Impurities

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Rapid Impurity Assessment

Option 1: Gamma spectroscopy • Requires samples at multiple time points (i.e.

over many days) Accurate and precise but not fast Requires analysis of complicated

emission spectra Option 2: Dose calibrator

with lead shield • Compare air and shielded samples • Similar method currently used to test for

moly breakthrough in generator-produced 99mTc1,2

• Establish a regulatory limit based on less than 10% increased dose at expiry

1. H. H. Lo et al., Radiology, 93(5), 1969. 2. P. Richards and M. O’Brian, J. Nucl. Med., 10(7), 1969.

Patient Dose Considerations

• Cumulative dose increase over pure 99mTcO4

- Proposed limit: <10% over

pure 99mTc

• Worst case scenario: thick target, 12 hr bombardment, dose at 24 hr > EoB Proposed 18 hr shelf life

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PETtrace Process Validation Batch Analysis

34 52 53

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TR19 Clinical Batch Analysis

Impurity T1/2 Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Sample 7 Sample 8

Tc-93m 43.5m <LOD <LOD <LOD <LOD <LOD <LOD <LOD <LOD Tc-93g 2.75h 16.4±0.7 7.7±0.8 27±2 22.5±0.7 4.1±0.2 9.9±0.4 3.7±0.2 35±2 Tc-94m 52m <LOD <LOD 220±20 140±18 71±9 87±9 110±10 <LOD Tc-94g 4.88h 21.6±0.8 30±2 33±2 29±1 17.3±0.6 16.5±0.6 23±1 31±1 Tc-95m 61d 0.088±0.004 0.077±0.008 0.15±0.01 0.140±0.005 0.083±0.002 0.056±0.001 0.076±0.004 0.120±0.003 Tc-95g 20h 15.1±0.6 17.7±0.8 25±1 21±1 12.8±0.8 10.3±0.5 16.3±0.8 21.1±0.7 Tc-96m 51.5m <LOD <LOD 560±70 580±83 <LOD <LOD <LOD <LOD Tc-96g 4.28d 3.7±0.1 7.3±0.3 6.4±0.3 6.1±0.3 3.4±0.2 4.80±0.08 4.0±0.2 4.9±0.1 Tc-97m 91.4d 4.2±0.2 4.0±0.2 6.0±0.2 8.6±0.4 4.5±0.2 4.2±0.1 4.4±0.2 4.7±0.1 Mo-99* 65.9h 0.57±0.02 0.73±0.04 0.05±0.01 0.31±0.06 0.32±0.01 0.172±0.009 0.51±0.03 <LOD Re-181 20h 2.0±0.2 <LOD 2.0±0.1 4.2±0.8 3.31±0.09 4.3±0.5 3.8±0.4 5.2±0.6

Re-182m 12.7h 2.3±0.1 0.77±0.09 3.4±0.4 5.7±0.4 5.3±0.5 4.3±0.3 3.1±0.3 5.3±0.5 Re-183 70d 0.024±0.001 0.018±0.001 0.056±0.001 0.072±0.003 0.043±0.002 0.054±0.002 0.046±0.002 0.086v0.002 Re-184 38d 0.005±0.001 0.004±0.001 0.008±0.001 0.018±0.008 0.012±0.001 0.013±0.001 0.017±0.001 0.026±0.001 Total (Bq/MBq) 66±1 68±2 877±73 816±86 122±9 141±9 168±12 107±3

Radionuclidic Purity (%) 99.99 99.99 99.91 99.92 99.99 99.99 99.98 99.99

QRT Ratio 194 420 249 158 182 145 246 365 Dose Increase (%)

At expirey 0.25 0.38 0.41 0.41 0.23 0.27 0.27 0.32 Yield (GBq) 17.0 34.8 19.7 36.0 19.5 21.3 29.8 20.5

Impurities are in Bq/MBq of 99mTc. LOD is limit of detection

Summary

• Regulatory process well underway – Pre-CTA consultations with Health Canada

• Issue: Tc-99m approved in Canada as a medical device • Overall sentiment: 2 small patient cohorts, data for 3 different

kit formulations (cationic, anionic, neutral) – Current status: CTA and REB approvals in Vancouver,

London; Hamilton on standby – 60 patient trial: 29/30 bone completed, 1/30 thyroid – Pre-NDS discussions underway – Full NDS submission anticipated end of 2016

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Moving Forward…

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ARTMS Value Proposition

ARTMS 99mTc Production System

• Reliable, ’green’ supply of 99mTc • Reduces reliance on HEU • Avoids single point of failure supply chain

• Supply independence and logistical compatibility

• Local control, responsive to market needs • Well-suited for geographically

concentrated patient populations • Multiple revenue sources • Competitive team, technology

• Protected by multiple patent applications

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Milestones and Deliverables

• Next 6 – 12 months: • Complete clinical trial in Canada and submit New Drug Submission • Obtain ISO 9001 certification and establish routine production capacity • Establish market development partnership with non-Cdn provider

• Next 12 – 24 months: • Establish OEM supply contract with global cyclotron manufacturer • Establish licencing/partnering arrangement in additional jurisdictions

R&D Prototype and Testing

Clinical & Marketing

Approval and Sales

2009-2011 2017 + 2012-2014 2015-2016

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Summary

• Regulatory – Nearing NDS submission

• Commercialization – Sole license issued to ARTMS Products Inc. – Advanced discussions underway with BC health service provider – ARTMS has nearly completed seed funding round, negotiations with

first customer • Emerging shift in 99mTc production

– Reactor-based supply and processing likely to maintain sufficient capacity, next 2 years are critical

– Several alternatives in development (n, p+ and e-/γ) – Full cost recovery must be implemented

• Despite this, cyclotron produced Tc-99m is price competitive today

Acknowledgements • The Team:

PIs: F. Bénard, T. Ruth, A. Celler, J. Valliant, M. Kovacs, Ken Buckley, Vicky Hanemaayer, Brian Hook, Laurel Stothers Stuart McDiarmid, Stefan Zeisler, Frank Prato, Joe McCann Anne Goodbody, Joe McCann, Conny Hoehr, Tom Morley, Julius Klug, Philip Tsao, Milan Vuckovic, Patrick Ruddock, Maurice Dodd, Guillaume Langlois, Wade English, Xinchi Hou, Jesse Tanguay, Jeff Corsault, Ross Harper, Costas Economou, Joel Kumlin, Jason McEwan

• TRIUMF and BCCA machine shops • Finances/Admin

– Mike Cross, Travis Besanger, Henry Chen, Francis Pau, Jenny Song, Steven Foster, Frank Gleeson, James Schlosser, Jim Hanlon, Ann Fong, Neil McLean, Kevin McDuffie, Niki Martin, Karen Young, Anthony Lam

Thank you! Merci!

pschaffer@triumf.ca